ABSTRACT Impaired cognitive function after common surgical procedures is a growing concern especially among over 5 million people in the United States who suffer from dementia, including Alzheimer's disease (AD), and thus have a 3-fold increased risk for fracture requiring surgical repair. After orthopedic surgery, acute changes in cognitive function, often referred to as postoperative delirium, occur in up to 89% of patients with preexisting dementia, and associate with poorer prognosis and even 2-fold greater risk for 1-year mortality compared to patients without dementia or delirium. Our long-term goal is to define the mechanisms that underlie surgery- induced cognitive dysfunction, and to provide safe and effective approaches to reduce this potentially devastating complication. In the proposed study, we will model postoperative delirium superimposed on dementia by subjecting mice with cerebral amyloid angiopathy (CAA), which is common in AD patients, to orthopedic surgery (tibial fracture). Our overall objective is to determine the role of the blood?brain interface (the neurovascular unit (NVU) and the blood-brain barrier (BBB) within) and vascular ?-amyloid deposition in cognitive function after orthopedic surgery in CAA mice. The central hypothesis is that surgery-induced BBB/NVU dysfunction is worsened in the presence of CAA, and that this is potentially preventable by regulating microglial function, which in turn, can impact postoperative cognitive outcomes. This hypothesis is based on preliminary data acquired in the applicants' laboratories, and will be tested by pursuing 3 specific aims: 1) Analyze BBB/NVU dysfunction in a CAA mouse model after orthopedic surgery; 2) Define the extent to which systemic inflammation and monocyte infiltration impact microglial function in CAA mice after orthopedic surgery; and 3) Determine the effects of an MLK3 inhibitor on microglial function, vascular ?- amyloid deposition, and cognition in CAA mice after orthopedic surgery. Feasibility for these models and techniques has been established in the applicants' hands. In this innovative approach, real-time in-vivo brain imaging and postmortem analyses will be combined with unbiased profiling of the neurovasculature and novel behavioral assays to define delirium-like changes in dementia-prone mice. The rationale for the proposed research is that successful completion will advance and expand our understanding of how surgery affects the blood-brain interface, and will provide new molecular mechanisms of relevance to delirium, neurodegeneration, and aging. Such knowledge is highly significant because it has the potential to improve surgical outcome and quality of life for millions of elderly vulnerable patients in the United States.